Is ACO2 p.Val25= (c.75C>T) pathogenic?

ACO2 p.Val25= (c.75C>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-01-01). Very rare (popmax 0.000339%, nfe); Associated with optic atrophy 9.

What condition is associated with ACO2 p.Val25= (c.75C>T)?

ACO2 p.Val25= (c.75C>T) is associated with optic atrophy 9, neurodegenerative disease (ClinVar).

How common is ACO2 p.Val25= (c.75C>T) in the general population?

ACO2 p.Val25= (c.75C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

ACO2 p.Val25=

c.75C>T · rs1057518833 · VCV374009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

optic atrophy 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.45, phastCons 1
Overall
CADD	10.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,030 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,830 alleles · very rare exomes 4/1,461,498 · genomes 0/152,332 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACO2
Protein: p.Val25=
Coding: c.75C>T
MANE Select: NM_001098
dbSNP: rs1057518833
Type: single nucleotide variant
Location: chr22:41499764 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44

Full ACO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

optic atrophy 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodegenerative disease

Similar variants

ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Glu321Lys Uncertain significance ★★ ⚠ same condition
ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 c.1032+17C>T Benign ★★ same condition
ACO2 c.1370+48A>G Benign ★★ same condition
ACO2 c.174-52G>T Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aco2-p-val25 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown